TRADE NAME: Lupron Depot, 4 Month, 30 mg

CENTER FOR DRUG EVALUATION AND RESEARCH

APPROVAL PACKAGE for:

APPLICATION NUMBER: 020517/S002

TRADE NAME: Lupron Depot, 4 Month, 30 mg

GENERIC NAME: Leuprolide acetate

SPONSOR: TAP Holdings, Inc.

APPROVAL DATE: 05/30/97

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DEPARTMENT OF HEALTH & EIUMAN SERVICES

PUbIic Hdth Sewi=

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NDA 20-5 17/S-002 Food

and Drug Adminlstrat~n

Rockville MD

208$7

TAP Holdings, Inc.

Artention: Aruna Dabholkar, M.D.

Associate Director, Rcgulatoty Affairs

MAY 30 W?’

235s Waukcgan Road Deerfie!d. IL 60015-1595 Dear Dr. Dabholkar:

Please refer IOyour new drug application dated May 30, 1996, received May 31, 1996, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Lupron Depot (Ieuprolide

acetate), 4-month. 30 mg. .

We also refer to your submissionsdated July 12 and September 30, 1996; Januaty 9, March 20, April 7. May 8.9, 27, 29 and 30, 1997.

The User Fee goal date for tis application is May 31, 1997.

This new drug application provides for a 4-month dosage form to be used for the palliative treatment of advanced prostatic cancer.

We have completed the review of this application and have concluded that adequate information has been presented to demonstrate that the drug is safe and effective for use as recommended in the final printed labeling submitted on May 30, 1996 (c~on ad container label~) ad May 3011997 (PhYsici~

and patient package inserts). Accordingly, the application is approved effective on the date of this letter.

In addition. please submit three copies of the introductory promotional material that you propose to use for this product. All proposed materials should be submitted in draft or mock-up form, nor final print.

Please submit one copy to this I)ivision and two copies of both the promotional material and the package insett directly to: . .

Food and Drug Administration

Division of Drug Marketing, Advertising and Communicxions~

HFD-40

5600 Fishers Lane

Rockville, Maryland 20857

Please submit one market package of the drug produce when it is available.

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NDA 20-517/S-002 Page 2

We remind you that you must comply with the requirements for an approved NDA sec forth under 21 CFR 314.80 and 314.81.

If you have any questiom, please contact

AIvis

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Dunson, Consumer Safety ~]cer, at (301) 8274260.

Lisa D. Rarick, M.D.

Director

Division of Reproductive and Urologic Drug Products

Off~ce of Drug Evaluation U

Center for Drug Evacuation and Research

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OfUJG SMIES IN H)IA7RIC PATIEhlTS

(To b CO@etad fO~ ti ~’s ~d for appmvd)

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‘A’*’ ‘ra&(-m)-s ““oo’.%’~f~~fl%’” ‘e’”e)

Check any of the foJJowlng that apply and~lain, as necessary, on the next page:

1.

2.

3.

h proposed -in the

draft labe~ng 3s

oirecteu

towara a

specific pediatric illness.

The application..contains adequate and well- contxo~ed studies in pediatric patzents .tn s~port that clalm.

The draft Labeling includes pediatric dosing information that is not basea on aaequate and weh-contmhu stuoies in cniidren. Tne application contains a request under 21 ER 210.58 or 3L4.U6(C) for wuver of the requirement at Z U% 201.57(t’) fot A&wCstuuies in

children. “ “

a.

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b.

Pediatric

The apptiatian contains data showing

that

the=ourse of’the disease and the effects of the arug’are suft’ide~tly similar in aaults ma cniloren to permit extrapolation

Or me

aata from adults to children. The waiver requescstwla De grantea ana a statement ta cnac effect is imluoeo *n the action letter.

The information incl.uaea in me app~cation aoes not adequately support the

^waiver

request. Tne request

should

nOt

be granted am a statement to tnat effect as inciuoea in the action Letter. (Cmplete #3 or *4

aelaw

as appropriate. j

.

stuaies (e.g., dose-YincQng, @macotinetic.

daverse

.

,-.

reaction, aclequate ana well-contrdliu ?or safety and 6fficacy) snou~o De done after

approval. The arug pmaucc has some

Dotentlal rm use in children, but there is no reatin to expect early’ widesmeaa —-—

f3eCliatriC

use

(because, fOr exan@e$ alternative ClkugS & available or the condition is uncammn in cniloren).

a. The applicant has comnlttea to doing sucn studies as

will oe

—.

required.

(U Stuaies are ongoing.

— (?) PrOt=OIS have been submitted and approvea;

(>J ~~~~~s ~ve oeen submittea am are

unoer

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(4) if’ no protocol nas been su~ittea, on me next -

page

explain tne status or discussions.

D. If tne sponsor is not wiUing to ao ped~atri~ stuaies, /

/

attach copies of

FGA’s

written request that.such

stuaies De *.

aone am of me sponsor’s written response tp mat request.

.

4. Rmiatric stuaies do not need to be encauragea because

tne

drug ‘

proauct nas little potential for use in chilaren.

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Page 2 -- .,

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Urug Studies in Pediatric Patients

If none ot . tne aoove apply, expiain.

Explain,

as necessary, the foregoing items:

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cc:

Orig

NUA

WD-_/Div File NUA Action

PacKage

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NDA 20-5 17/S-002 {

[

Lupron Depot” (Ieuprolide acetate for depot suspension) 4-month, 30mg

Adwwtising Material No ad~ertising material has been submitted. -

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NDA 20-517/S-002

Lupron Depo@ (leuprolide acetate for depot suspension) 4-month, 30 mg

Federal Register Notices z

This application was not the subject of any Federal Register Notices.

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NDA 20-5 17/S-002

Lupron Depot” (leuprolide acetate for depot suspension) 4-month, 30 mg

Advisory Committee Meeting Minutes - —

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This application was not the subject of an Advhmy Committee Meeting.

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NDA 20-517/S-002

Lupron Depo@ (leuprolide acetate for depot suspension) 4-month, 30 mg

DSI Audit of Clinical Studies .

No clinical audits were necessary as determined in-the fding meeting held June 25, 1996

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NDA 20-517/S-002

Lupron Depot@ (Ieuprolide acetate for depot suspension) 4-month, 30 mg

Division Director’s Memo

This a~lication- will be signed off at the Division level. No memo is necessary.

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NAY

30 ~

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NDA:

Drug and indication:

z

Dose: .

Applicant:

Submission dated:

Date of MO review:

Date of Memorandum:

Group Leader Memorandum 20-517/S-002

Lupron Depot* (leuprolide acetate for depot suspension) 4- month, 30 mg for the PaUiative treatment of advati

prostatic cancer:

one iqjection of 30 mg every 16 weeks Tap Holdings, Inc.

my 30, 1996 May 9, 1997

May 29, 1997

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In this application, the sponsor requests approval for a four month depot formulation of the

approved drug leuprolide acetate. The primary source of evidence supporting the safety and - efficacy of this product is the results of a single, multi-center, u.hcontrolled open-label study

conducted in 49 men with advanced prostate cancer. Based on this study’s results and comparisons to historical data, it appears that the safety and efficacy of this formulation are similar to that of other leuprolide depot formulations approved for palliative treatment of advanced prostate cancer. I concur with the recommendation of the primary reviewers that this application is approvable.

Two recommendations for phase IV studies were made by the Biopharrnaceutics and Clinical reviewers, respectively. In the Biopharmaceutics review, a phase IV study was suggested to assess multidose Ieuprolide pharmacokinetics in the target population. However, following subsequent internal discussion of this issue, it was agreed that this requirement could be waived because accumulation of leuprolide following multiple administration is unlikely to be clinically significant and because the pharmacodynamic effect of multipledosing has been evaluated in the target population. In the Clinical review, Dr. Golden discusses the clinically important issue of acute testosterone “flare” reactions upon treatment initiation and

recommends a study to evaluate the efficacy of concomitant anti-androgen administration in preventing these reactions. However, because this clinical question involves multiple

sponsors, the Division will not require this study as a phase IV commitment from this sponsor at this time. The Division should have further internal discussion to determine how best to encourage development of ant.i-androgens for this indication. -

The majority of substantive labeling issues have been adequately addressed by the sponsor at

the time of this memorandum. Two labeling issues merit commen~ -.

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flDA 20-517/ S-002 Gro D J,eader Memora u n dam Paze 2 “ First, it should be noted that the Indications and Usage seetion has been revised to omit

the statement,

. a ‘I%is

statement was omitted because: 1) it is vague and subjeet to interpretation; +) it is

‘outdated since estrogen is no longer the standard of care and GnRH agonists are widely used; 3) the choice of surgie.al or medi-&l palliative treatment should be an

individu@ed decision made by the patient and their health care provider and should be based on the respective (and quite different)& and benefits of each treatment; and 4) practice recommendations that take into account factors such as cost and compliance should be made by the appropriate profmsional societies and not by FDA. For consistency, labels for other leuprolide and goserelin formulations should be similarly revised.

Second”, because Ieuprolide is used for urologic and gynecologic indications at”<

considerably different doses, the header of all leuprolide labels should contain a prominent statement regarding whether the drug is intended for men or for women. A request for this revision will be made post-approval. .—

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Heidi M. Jolson, “ M. D., M.P.H.

Deputy Division Director, HFD-580 cc:

NDA20-5171S-002

HFD-580/LRarick/LGolden/HJolson c:\h\20517-2.gl

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MAY30 jgq

MEDICAL OFFICER’S ADDENDUM to REVIEW OF NDA SUPPLEMENT (S-002)

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NDA # 20517 (S-002) Submission Date (via e-mail): 5/27/97

Sponsoc TAP Hokii.ngs hlC. Receipt Date: 5/27/97

User Fee Goal Dam 5/31/97 Date Review Completed: 5/28/97 z

This pending NDA supplement for Leuprolide acetate for &pot suspension (Lupron Depot 4 Month 30 mg) was previously reviewed (refer to MOR dated 5/9/97). The sponsor now submits revised draft labeling (via e-mail ord~ hard copy not yet received) in response to DRUDP’S labeling comments conveyed to the sponsor by letter dated 5/23/97.

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REVIEWER’S COMMENT Son REVISED DRAFT LABELTNG - --

Recommended revisions are briefly described below. Refer to handwritten comments on atta~hed draft labeling for details of suggested revisions.

Description

Text should be added to this section to clearly indicate that this formu.latkin is for use - by men only. This revision maybe made by post-approval supplement and should

also be implemented, as appropriate

depending on approved indications) for all other affected Lupron formulations.

Clinical Pharmacology

Refer to handwritten comments for suggested clarifications to paragraph 2 of Clinical Studies subsection.

Indications and Usage

The

previously deleted second sentence, L’

s

shotdd be restored to this secrion of the labeling.

Thk recommendation i based on the following

(1) All other approved Lupron labeling for prostate cancer contains the above statement, as does currently approved labeling for Zoladex (goserelin acetate implant) for prostate cancer, based on

previous Advisory Committee recommendation (per today’s discussion wkh Dr. Jean Fourcroy, . . Medical Officer, DRUDP).

(2)

The sponsor has not requested the removal of the above statement and has not submitted any scientific or clinical justification for its removal.

In addition, this reviewer is not aware of any scientific

or clinical documentation that would justify its removal on an efficacy or safety basis.

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NDA#20-517 (S-002) Page 2 -

Addendum 10MORofNDAEfficacySuppkmm S/2S/97

(3) Recent medical literature (Pofier AT et al: Recommendations of the First Michigan Conference on Prostate Cancer. Urology 1996; 48:519-534) conch&s that the primaxy therapy for symptomatic metastatic prostate cancer is “androgen deprivation therapy,” with bilateral orchiectomy (surgical castration) and GnRH agonist therapy (medical castration) considered alternate treatment choices.

Since severe “flare” reactions (obsemed in 15% of patients in the pivotal clinical trial for Lupron Depot4 Month 30 mg) during the f- 2-4 weeks of GnRH agonist therapy may be life-threatening and do not occur after bilateral orchiectomy, this reviewer concurs with the designation of

orchiectomy as the “gold standard” treatment modality for this disease. The restored 2-sentence indication statement (which implies that GnRH analog therap y is second-line treatment) is consistent

with this observation. *-

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(4 Proposed expansion of the labeled indication from treatment

(by deleting the second sentence above) should be supported by eithen ; (A) Documentation of an adequate scientific rationale for such change,

based on clinical safety/efficacy&~ or .—

(’B) Recommendation of a specially constituted

Advisory Committee with special expertise in urologic oncology.

Warnings

For consistency with currently approved Zoladex (goserelin acetate implant 3.6 mg, Zeneca Pharmaceuticals) labeling, the last sentence should be revised to read:

Precautions

The sponsor

should be asked to provide clarification of the actual clinical obsenation

period for orchiectornizd patients in the Clinical Pharmacology study

(i.e., 16 or

20 weeks), and to correct the text accordingly, as indicated.

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Information for Patients

See attached consult repoxt from

Louis Morris, DDMAC, for numerous comments on the

proposed PPI, all of which should be conveyed to the sponsor. ,.

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NDA#20-517 (S-002) Page 3 -

Addendum to MORofNDAEllicacy

Supplement 5/28/97

In addition, this reviewer has the

following coxnmsnts regarding page 7 of the PPI:

~) The last sentence above the, section shotild be rm-sed

to reack *

(2) The section entitled

should be.deleted

for consistency with the physician labeling.

Adverse Reactions

This section has been greatly improved and is now acceptable as proposed.

Dosage and AdministratiorI

The following clarification is still needeck

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CONCLUSION

The revised draft labeling is significantly improved from previous versions but still needs a few substantive modifications, as described above.

RECOMMENDED REGULATORY ACTION

The suggested labeling changes detailed above and handwritten into the draft document should be conveyed to the sponsor, including those from DDMAC.

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rziyj+ -

Lin&

J.

G~den, M.D.

Medical Officer,

HFD-580, DRUDP

Attachments: Lupron Depot 4 Month ~0 mg Draft Labeling Revision dated 5/27/97

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cc: Original NDA Arch HFD-580

HFD-580/LRarick/HJolson/ADunson -.

HFD-580/ LGolden (+ attachment) /JFourcroy (+ attachment)

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MEDICAL OFFICER’S REVIEW OF NDA SUPPLEMENT (S-002)

NDA # 20-517 (S-002) Original Submission Date:

5/30/96

Sponsor: TAP Holdings Inc. Filing Date: 7/30/96

1.C Ge$erai Information

e of

Generic n~me:

Proposed trade name:

Chemical name:

Date Assigned to M. O.: 8/29/96 User Fee Goal Date: 5/31/97 Date Review Completed: ~ 5/%’97 .

Leuprolide acetate for

depot suspension Lupron Depot -4 Month

30 mg

Oxo-L-pro1yl-L-histidy1-L-t~prophyl-L-se~l-L-tyrosyl-D-leucyl-

L-Ieucvl-L-arzinvl-N-ethvl-L-~rolinarnide acetate &lt).

1 $Oi+ ^{~yfHOHOH OHOH} ?~oH

C-N-"CH-C-N-CH-C-h-$ +t-h-~H-:-h-:+i -h-C+~-h-CH-C-N-

:

&+ “ &iJ-CH$& -1-2CH3COOH

CHZ $Hz

H :Hz CH2 p+z Cl-lz c~

,> N-H OH

o

CH3<H cH3-~H $&

~J I C& CH3 ~l+z - _

N–H

OH $ -NH

Nb$

J’harmacoloz ic Cate.~u H Synthetic nonapeptide agonist analog ot

the

naturauy occurring gonadotropin releasing-hormone (GnRH or LH-R~

J’roposed Indicmion Palliative treatment of advanced prostate cancer.

Dosage Form . . .

and Roure of Ad~

Depot suspension for intramuscular (IM) injection @J dose of 30 mg every 16 weeks (every 112 days).

The 30-mg depot formulation package consists of a single-dose vial containing Iyophilized

rnicrospheres of leuprolide

(3o mg) incorpora~ed into a biodegradable lactic acid polymer and a 2-ml ampule of diluenr; this

dosage is based on 7..5 mg per month (dose for monthly depot) over 4 months.

yD~ DmF Classification

3s

Leuprolide acetate Injection (Lupron, TAP): NDA #19-010 Leuprolide acetate Depot (Lupron Depot, TAP):

IND NDAs %19-732, 19-945,20-011, 2C-265, 20-708 Goserelin acetate (Zoladex, Zeneca): ND.+ = 19-726 Nafarelin acetate (Synarel, Searle): ND.+ 419-886 Histrelin hcerare (Supprelin, Roberts Labs): NDA #19-836

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Chemistry Review dated 4/lj/97 - Pharmacology Review’ dated 6/ 14/96

Clinical Pharmacology and Blopharmaceutics Re\-iew dxed 2/.20/97 -.

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NDA #20-517 (5-002)

MORof NDA Efficacy Supplement, 5/9/97

Page 2

2.o Table of Contents 3.0

4.0 5.0 6.0

7.0 8.0

9.0

Material Reviewed

Chemistry/Manufacturing Controfs

Animal Pharmacology/Toxicology ‘

Clinical Background .

6.1 6.2 6.3 6.4 6.5 6.6

Relevant human experience

Important information from related IND’s and NDA’s Foreign experience

Human pharmacology, pharmacokineties, pharmacodynamies Other relevant background information

Directions

for

Use

Desm”ption of Clinical Data Sources CiinicaI Studies

8.1

Indication

8.1.1 Reviewer’s Trial #1: Sponsor’s Protocol #M93-ol3 8.1.1.3 Protocol

8.1.1.3.3 Endpoints

8.1.1.3.4 Statistical analysis plan 8.1.1.4 Results

8.1.1.4.2 Efficacy Endpoint Outcomes 8.1.1.4.3 Safety Outcomes

8.1.1.5 Conclusions regarding Efficacy Data

8.1.2 Reviewer’s Trial #2: Sponsor’s Protocol #M93-012

Overview of Eficacy

10.0 Overview Of Safety

10.1

10.1.1 10.1.2 10.1.3 10.2 1C,2.1 lc. ~ ~ --- 10.2.3 10.2.4 10.2.5 10.2.6

12.2.7 1S.2.8

Significant/Potentially Significant Events Deaths

Other Significant/Potentially Significant Events Overdose Experience

Other Safety Findings ADR Incidence Tables

Laboratory Findings, V:tal Signs,

EKG’s

Special Studies

Drug-Demographic Interactions Drug-Disease Interactions Drug-Drug Interactions

Withdrawal Phenomena/Abuse Potential Human Reproduction Data

11.0 Labeling Review - ,

12.0 Conclusions 13.0 Recommendations REFERENCES

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I?my of

MOR

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3 4 5 5 7 9 9 10

11 JI 12 12 12 12 14 16 17 24 31 38 39

40 41 41 41 -42

42 42 42 43 43 43 43

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43 43 44 46 47 . 47

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NDA #20-517 (S-002)

MOR of N13AEfficacy Supplement, 5/9/97

3.0 Material Reviewed

Page 3 .

Volume 8.1 ,

Volume 8.6 ~

Volume 8.7

Volume 8.8 Volume 8.9

Volumes 8.10-8.11 Volume 8.12

Volumes 9.1-9.4 Volumes 11.1-11.2 Volume T53049

Volume T57618

Table of Contents and Application Summary, 5/30/96 — Section IV. Human Pharmacokinetics and Pharmacodynamics Section:

Table of Contents, Study Report.of Clinical Pharrnacokinetics Study M93-012 Section V. Clinical/Statistical Section:

Table of Contents, List of Investigators/IND’s, Study Report of Open-label Clinical Trial M93-013

Section V. Clinical/Statistical Section Individual Patient Data

Integrated Summary of Safety, Integrated Summary of Benefits and Risks, Post-Marketing Studies, 21 CFR314.50(d)(5)(ix), (x) a (xi)

Case Report Form Tabulations for Study M93-013 . ——

Case Report Forms for Discontinuations due to Adverse Events, Deaths or Disease Progression for Study M93-013

Amendment #’2: 4 Month Safety Update Report, 9/30/96

Amendment #3: Additional Requested Case Report Forms, 1/9/97 Amendment #5: Initial Response to FDA letter dated February21, 1997, 3/20/97

Amendment #6: Funher Response to FDA letter dated February21, L997, 4/7/97

4.0 Chentist~/Manufactun”ng Controls

Please refer to the Chemistry Review.

Sponsor states (pg. 2 of application cover letter), “the microsphere [TAP- 144-MC(3M)] powder used for Lupron Depot-4 Month 30 mg product is the same as that used for our approved product Lupron Depot-3 Month 22.5 mg, with the exception of the additional weight of the powder packaged in a vial.” The additional drug quantity is intended “to provide adequate leuprolide blood ievels over

16 weeks.” Sponsor notes that the clinical and pharmacokinetics studies submitted to support this supplemental application were conducted using the Lupron Depot-4 Month-30 mg product proposed for marketing.

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The depot formulation package contains asingle-dose vial containing lyop~ilized powder anc+an ampule of diluent. It may be stored at room temperature until administered. -

NDA #20-517 (S-002)

MOlt of NDA 13Tmicy Supplement. 5/9/97

Page

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5.0 Animai Pharmacology/Tom”co!ogy

Please refer to the Pharmacology Review.

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a. Pharmacodynamics e

(I) Primary pharmacologic classification and mechanism of action:

Leuprolide acetate is a synthetic gonadotropin releasing hormone (GnRH) agonist analog which possesses greater potency than the natural hormone. When given continuously in therapeutic doses, it acts as a potent inhibitor of gonadot repin secretion. Chronic

administration to animals and humans results in an initial stimulation, then prolonged suppression of ovarian and testicular steroidogenesis which is reversible upon discontirmation of drug treatment. In rats, Ieuprolide acetate administration results in growth inhibition of certain hormone dependent tumors (prostatic tumors in Noble and Dunning male rats and MBBA-induced mammary rumors in female rats) and atrophy of the reproductive organs.

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(2) Other Actions: None known.

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(3) Results of human studies (per 12/21/95 MOR of NDA #20-517 for Lupron Depot-3 Month 22.5 mg and its currently approved labeling):

Leuprolide acetate administration to humans results initially in increased circulating levels of Iuteinizing hormone (M-I) and follicle stimulating hormone (l%m, with correspondingly increased levels of the gonadal steroids, testosterone (T) and dihydrotestosterone (DHT) in males, and estrone (E1) and estradiol (Q in pre-menopausal females. Ongoing continuous administration then results in decreased levels of LH and FSH, with corresponding reductions in sex steroid levels (T in males, and estrogens in pre-menopausal females) to the castrate range wi~hin two to four weeks after treatment initiation. In prostate cancer patients, castrate levels of testosterone have been demonstrated with continuous administration for periods of up to iwe years.. .

Leuprolide acetate is not active when given orally.

b. Pharmacokinetics (per 12/21/95 MOR of NDA #20-517 and currently approved Iabelirig)

. .. . (1) Blood level data in humans:

Absorption: Following a single IM injection of the 3-month formulation (Lupron Depot 22.5 mg) in patients, the mean peak plasma leuprolide concentration was 48.9 rig/ml at 4 hours, which declined to 0.67 rig/ml at 12 weeks. The onset of steady-state levels was obsem.ed during the third week after dosing, u’hen leuprolide appeared-to be released at .1 consran~ rate with steady plasma concentrations through the 12-week dosing intend,

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NDA #20-517 (S-002)

MOR of NDA Efticacy Supplement,5/9/97

Page 5 -

Although the assay employed in the study could not distinguish intact Ieuprolide from an inactive major metabolize, leuprolide levels remained detectable at all measurement points in all patients. The release pattern of an initial burst followed by rapid decline to a ste=y-state Ievel was similar to that seen with

the

monthly formulation.

*

Distribution: In healthy male volunteers, the mean steady-state volume of distribution was 27 L and the mean systemic clearance was 7.6 L/hr following a

1

mg intravenous (IV) bolus dose of leuprolide. The terminal elimination half-life was approximately 3 hours based on a 2-compartment model. In vitro binding to human plasma proteins ranged from 90.

Metabolism: In 5 prostate cancer patients, the major metabolize (Metabolize-1, a pentapeptide)

*- reached maximum plasma concentrations 2 to 6 hours after dosing at approximately % of the

peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately ‘h of mean leuprolide concentrations. [Rats and dogs metabolize administered 14C-labeled Ieuprolide to smaller inactive peptides, the pentapeptide M-I, tripeptides

(Metabolizes 11 and III) and a dipeptide (Metabolize IV), all of which may be further

catabolized.] .— -

(2) Excretion: Following administration of Lupron Depot 3.75 mg to 3 patients, less than “/0 of the dose was recovered as parent and M-I metabolize in the urine.

(3) Special Populations: ‘“ “ ‘ “ ‘ ‘ “ “ “ ‘ “ ““ “ “. “ “

patients have not been c. Toxicology:

1 he pharmacokmetx.s ot the drug m hepatlcally and renally Impaired determined.

Refer to Pharmacology Review.

6.0 Clinics! Background

6.1

Relevant human experience

a. Pre\rious similar human studies (Refer to section 6.2 below for information regarding appro~~ed GnRH analog drugs other than leuprolide acetate):

Clinical studies of Ieuprolide acetate treatment of metastatic prostate cancer patients (by daily subcutaneous and monthly IM depot injections) have shown that serum testosterone (T) is effec~ively suppressed after two to four weeks of treatment to a range similar to that observed in surgically castrate patients. This “medical castration” appears to be mediated by

desensitization of the pituitary to stimulation by native GnRH with resulting suppression of gonadotropin release. Gonadal testosterone production is secondarily suppressed, with corresponding reduction of circulating T to castrate levels. The resulting androgen deprivation mav cause both primary and metastatic androgen-dependent tumor proliferation to slow, stabilize, or regress, with possible reduction in pain related to metamatic skeletal lesions.

In TAP-sPonsored clinical studies of advanced pros~ate cancer, the sponsor has repot-ted favorable objective responses in 72°/0to 86°A of Lupron-treated patients, with most -=

improving/stabilizing on Eastern Cooperative Oncology Group @-COG) performance status,

NDA #20-S 17 (S-002)

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MOR of NDA Efkcy Supplement 5/9/97

The extended release depot formulation containing 22.5 mg of leuprolide (for administration at 12 week intervals) was studied in two pivoial safety and efficacy trials (#M9 1-583and

#M9 1-653), conducted to support marketing approval of NDA #20-5 17. The prima~ pivotal

;afety/efficacy trial (M9 1-583) studied 60 patients with Stage D2 (metastatic) prostate cancer.

The objective of the secondary trial (M91~3) was to demonstrate therapeutic equivalence of the clinical formulation (of pilot plant manufacture) studied in

M9 1-583 to the formulation proposed for marketing. Study M9 1-653 enrolled 33 patients with Stage D2 prostate cancer.

Both studies were open-label, uncontrolled, multicenter trials (18 centers, of which two participated in both trials) of nearly identical design, in which the 22.5 mg depot formulation

was administered as an IM injection every 12 weeks (84 days). The primary efficacy endpoint .- was serum T level suppression and maintenance, from baseline to castrate levels (defined as

50 ng/dl

or less), as assessed by weekly blood sampling for 24 weeks. Study M9 1-583 included an expanded blood sampling schedule for a subgroup of patients, with serum LH and T; levels determined at half-weekly intervals during the last 2 weeks of the first two dosing periods and immediately following the week 12 depot injection. Clinical response to treatment and general safety parameters were assessed every 12 weeks. After the initial 24-week phase,

patients were continued indefinitely on the study, with serum

T

level monitoring every - 12 weeks, until clinical benefit was no longer evident.

NDA approval was based primarily on

the first 24 weeks data.

During

FDA

reviewof NDA #20-5 17, a discrepancy was noted in the reported serum T levels of treated patients. Despite T level determination by the same laboratory ~

that had assayed serum T concentrations for all prior TAP-sponsored Lupron trials in advanced-stage prostate cancer patients (i.e., Lupron administered by daily SC injection and by monthly 7.5 mg IM depot injection), on-treatment T values repotted for studies M9 1-583 and M9 1-653 were consistently higher (while still in or near the castrate range) than those reported from the prior TAP-sponsored Lupron trials. This prompted an

investigation of the discrepant findings, including re-examination of historical and contemporaneous T values of patients still active in the previous studies, and . re-assay/validation of numerous samples by two separate methods[ by both

routinely uses either of t~~o purification procedures to prepare serum samples for T levelquantitation by , methodology. The appropriate purification procedure is deter-mined by the range of T values expected in the samples to be assayed. Thus, a

procedure is sufficient to quantify T levels in the normal adult male range of approximately 300 ng!dl or higher.

,4 purification procedure in which extraction from the serum sample is folloived b>

is u[ilized [o enhance assaj sensitivity and precision for T level determinations near the caslrate range (approximately ng’dl or less). The respective lower limits of testosterone detection for.+e are 10 ng~dl after purification by the versus 3 ng/dl aft.ET .purtfication by [he

--

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The investigation concluded that the higher-than-expected T levels resulted from

inadvenent use of a method for the range

of T levels expected in the M9 1-583 and M9 1-653 clinical samples, due to a commutation

~rror between TAP Pharmaceuticals Inc. and Since T levels near the castrate range are expected with letiprolide administration, use of the more sensitive

is indicated to improve the accuracy of T level measurements in Lupron- treated pr6state cancer patients. To confirm this expkmation, all but 4°&of the M9 1-653 clinical samples were re-assayed using the for purification and the re-assayed T results were found to be consistent with prior Lupron

study data.

The reanalysis of studies M91-583 and M91-653, using

.- derived data, showed

that serum T was suppressed to castrate levels within 30 days in 87 of 92 (95°k) patients and within an additional two weeks in three patients. In two patients, however, T levels did not suppress “for15and 28 week, respectively. Once achieved, suppression was maintaine~ in all except two patients: one with transient minimal T elevations; the other with serum T above the castrate range during the first 12-hour period after a subsequent injection (suggesting

re-stimulation of gonadotropin secretion following a 12-week period of desensitization, -- referred to by the sponsor as an ‘acute-on-chronic” response). During the initial 24 weeks of

treatment, the sponsor reported an 85% rate of “no progression” and normalization of PSA values ( rig/ml or less) in 63% of the patients,

b. Literature references that are especially appropriate: None submitted.

6.2 Important information from related

IND’s and NDA’s

Lupron In;ection (leuprolide acetate 1 mg/O.2 ml for subcutaneous injection) was first approved in 1985 at the dosage of 1.0 mg SC daily for the palliative treatment of advanced prostate cancer. Lupron Depot (leuprolide acetate for depot suspension) – developed to provide prolonged continuous-

Ieuprolide release -- was first approved in 1989 as a 7.5 mg 28-day IM depot formulation, based on clinical study #M85-097, which demonstrated suppressed gonadal function in 53 evaluable treated patients with stage D2 prostatic carcinoma. In 1995, based on clinical studies #M91-583 and #M91-653 (see section 6.1, above), the 22.5 mg 3-month depot formulation was approved for IM dosing at 84-day intervals for palliative treatment of advanced prostate cancer.

The following formulations of Lupron have received FDA approval to date for the indications listed: , . . .

--

—.

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Product NDA # Approval Date Labeled Indication

Lupron=Injection 1 mg/O.2 ml ‘19-O1O 4/9/85 Advanced Prostate Cancer

*

Lupron Depot 7.5 mg/vial ‘19-732 1/26/89 Palliative Treatment of Advanced Prostate Cancer

Lupron Depot 3.75 mg/vial ~ 20-011 10/22/90 Management of Endometriosis

s-

Lupron Depot-PED ~20-263 4/16/93 Treatment of Central

7.5, 11.25, and 15 mg/vial 1/21/94 Precocious Puberty

Lupron Depot 3.75 mg/vial ~ 19-943 3/30/95 Treatment of Anemia ‘

Secondary to Uterine Fibroids

Lupron Depot-3 Month ~20-517 12/22/95 Palliative Treatment of -

22.5 mg/vial Advanced Prostate Cancer

Lupron Depot-3 Month A 20-70!3 3/7/97 Management of Endometriosis

11.25 mg/vial Pre-op Treatment of Anemia

Secondary to Uterine Fibroids

The approval of NDA #20-5 17 specified a Phase IV commitment requiring the sponsor to conduct a postmarketing study to further characterize the possible agonist effect of leuprolide following

re-injections and to compare the response associated with the l-month (28-day) and 3-month (84-day) depot formulations. On 9/13/96, the sponsor submitted a new protocol for study

#M96-458 ~Phase IV Study Evaluating the Agonistic Stimulation of Serum Testosterone Folkowing Re-injection with Lupron Depot-3 Month 22.5 mg and Lupron Depot 7.5 mg and Assessment of the PK/PD Relationship for Lupron Depot-3 Month 22.5 mg”) to satisfy this commitment. Sponsor stated that the multicenter, randomized, open-label study (M96-458) would be conducted in 60 advanced stage prostate cancer patients – 30 receiving ~ monthly doses of the 7.s mg formulation and 30 receiving 4 quarterly doses of the 3-month formulation – and would be initiated 3 to 4 weeks thereafter.

..- A second approved GnRH analog drug for palliative treatment of advanced prostate cancer is

Goserelin acetate (Zoladex, NDA #19-726, sponsored by Zeneca). Zoladex was first approved in 1989 as a 3.6 mg 2S-day subcutaneous (SC) implant, based on clinical evidence that the drug reduced mean serum T levels to the castrate range between treatment weeks 4 and 12, and that mean serum T levels remained suppressed at weeks 4, 8, and 12. In 1996, a 3-month (84day) 10.8 mg depot formulation-.

was also approved for treatment of advanced prostate cancer. In addition, the 3.6 mg depot formulation received approval in 1993 for monthly (28-day) treatment of endometriosis in ‘ premenopausal women.

—. -.

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GnRH analog drugs approved for indications other than prostate cancer include:

(1) Nafarelin acetate (Synarel Metered Nasal Spray, sponsored by Syntex, marketed by Searle):

NDA #19-886 approved 1990 for treatment of endometriosis, and . —

‘z NDA # 20-109 approved 1992 for treatment of precocious puberty.

*

(2)

Histrelin acetate (Supprelin, sponsored by RWJohnson/PRI, marketed by Roberts Labs):

NDA #19-836 approved 1991 for treatment of precocious puberty.

Native

gonadotropin releasing

hormone (GnRH) is also approved in two formulations:

(1)

Gonadorelin hydrochloride (’Factrel Injection, marketed by Wyeth Ayerst) NDA #18-123 approved 1982 for diagnostic use.

*-

(2) Gonadorelin acetate (Lutrepulse Kit, marketed by Ferring Labs):

NDA #19-687 approved 1989 for diagnostic use.

6.3

Foreign experience -— _

On March 20, 1997, the sponsor stated that the Lupron Depot-4 Month 30 mg formulation had never been marketed nor studied in clinical research in any country other than the

U.S.

6.4 Human pharmacology, pharmacokinetics, pharmacodynamics

Refer to Biopharmaceutics Review, which notes the following significant issues/recommendations:

1) The multiple dose pharmacokinetics (PK) of Lupron Depot-4 Month 30 mg have not been assessed in the target population for drug treatment;

2) The pharmacodynamic (PD) effect of Lupron Depot+ Momh 30 mg (suppression and - maintenance of serum T levels within the castrate range) appears similar to that shown for the approved Lupron Injection, Lupron Depot 7.5 mg, and Lupron Depot-3 Month 22.5 mg formulations;

3) As observed with the previously approved Lupron Depot formulations, no PK/PD correlation could be established for the Lupron Depot-4 Month 30 mg formulation.

4) The above issues may be addressed by a post-approval requirement for aPhase IV multiple dose PK/PD study in the target population, including assessment of both leuprolide and

testosterone levels after at least 3 administrations of the 4-month depot formulation.

The application references NDA’s # 19-010 (Lupron Injection 1 mg/O.2 ml) and #19-732 (Lupron Depot 7.5 mg/vial) for background information on the clinical pharmacology of Ieuprolide ace~ate.

The application includes the repofl of Study M93-012, a multicenter, open-label, clinical

pharmacokinetics study, conducted in 24 orchiectomized prostate cancer ~tients at s invest~ational sitesto evaluate plasma leuprolide levels following a single IM injection orihe Lupron Depot-4 Month

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30 mg formulation. PK findings from this study were reviewed by Dr. K. Gary Barnette, Biopharmaceutics Reviewer, Division of Pharmaceutical Evaluation II, Office of Clinical

Pharmacology and Biopharmacetnics. For safety information pertinent to this study, refe- section 8.1.2, below.

+

6.5

Other relevant background information

According to recent statistics published by the Ameriean Cancer Society (Parker SL et al, 1996), prostate cancer is the most common malignancy in US men with an estimated

1996 incidence of

317,100 new cases/year, accounting for 4i% of ‘all new invasive malignancies in American men.

,- Its course is unpredictable, ranging from an asymptomatic, indolent condition to a virulent

malignancy with rapid progression to bone metastasis and death (Garnick MB, 1993). Its 1996 mortality is estimated at 41,400 American men/year, which accounts for 14% of male cancer d~aths, making it the second leading cause of cancer mortality (after lung cancer) in American men. American males face a 1 in 5 overall lifetime probability of developing invasive prostate cancer, with markedly rising risk associated with increasing age, especially after age 50. In addition, African Americans are disproponionately affected by prostate cancer incidence and mortality, with an incidence of 264 per

- 100,000 African American men compared with 194 per 100,000 Caucasian men (lvlichigan Cancer

Statistics, 1995). For the year 1992, prostate cancer mortality comprised 9.4% of all cancer deaths (5485 deaths due to prostate cancer) among African Americans and 6.3% of all cancer deaths (28,430 deaths due to prostate cancer) amo;g Caucasians, By comparison, the proportion of 1992 cancer mortality due to female breast cancer was 8.3°k of cancer deaths among both Caucasian and African American women (37,797 and 4779 deaths due to breast cancer, respectively). The most important known risk factors for prostate cancer are age, race, and family history in a first degree relative (f~ther, brother or cousin). Current guidelines for prostate cancer screening (Porter AT et al,

1996) suggest a Digital Rectal Exam (DRE) and Prostate Specific Antigen (PSA) starting at age 40 for high risk men (i.e., men of any race with a family history of prostate cancer in a first degree relative, and all African American men) and at age 50 for all other men with a life expectancy of more_ than 10 years.

Since metast~tic prostate cancer remains incurable, the primary goals of treatment are to improve the quality of remaining life and to increase the time to progression and perhaps survival. With androgen deprivation treatment, 70% of men with metastatic disease will experience a symptomatic and often a clinical regression, but most will relapse within

18 to

24 months. In view of this short life expectancy, the most clinically significant endpoint of treatment is quality of life, especially regarding issues of immediate and long-term impotence, urinary symptoms including incontinence, degraded bowel function, p.~in, altered social function, and treatment-associated risks. Unfortunately, standardized, validated and well-accepted measurement instruments for these quality of life issues are still being

deveioped. ,

Despite the availability since 1985 of GnRH agonist treatment (Lupron Injection 1 mg/O.2 ml) for

“medical castration, ” and the availability since 1988 of combination leuprol~de/flutamide treatment for

“total androgen blockade,” orchiectomy has remained the gold standard for prostate cancer ~reatmen[.

“Total androgen blockade” remains controversial because of lingering ques[ions regarding t~ role of adrenal androgens in the disease process and the uncertain advantage of concomitant antiandrogen

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treatment. To address these questions, a systematic international meta-analysis was recently

undertaken of the available evidence, using individual patient data from 5,710 patients enrolled in 22 of the 25 known randomized trials with a “maximum androgen blockade” treatment arm (i.e.~ast ration plus an antiandrogen: flutamide, cyproterone acetate, or nilutamide) versus surgical or medical

castration alone.. Crude monality rates over a median follow-up period of 40 months, during which 3283/5710 or 57% of the patients died, were 58% for castration aione and 56% for “MAB.” Life-table estimates of the corresponding 5-year sumivai rates were 22.8% and 26.2%, respectively, indicating a non-significant sunival difference of 3.5% (95% CI O-7%) in favor of ‘MAB.” Since no obvious sources of bias could account for the results, the authors concluded that the available evidence from randomized trials did not demonstrate that “MAB” results in longer survival than conventional castration. (Prostate Cancer Triaiists’ Collaborative Group, 1995). A possible explanation for these negative findings may relate to the late effect of prolonged androgen deprivation (which causes prostate adenocarcinoma cells to become apoptotic) to facilitate the inevitable emergence of more undifferentiated; androgen-independent tumor cells. (Middleman MN et al, 1996). .

*-

Castrate serum levels of testosterone have traditionally been defined as less than so ng/dl based on

measurement in prostate cancer patients post-orchiectomy. However, this standard of surgical - castration was established, prior to the availability of highly sensitive technology, using methods

of lower sensitivity and specificity, including urinary ketosteroid excretion assays (which cross react with various adrenal androgens). With current assay methods, castrate levels of testosterone are usually considerably less than 50 ng/dl, as demonstrated by recent data from trials of Lupron and Zoladex for prostate cancer. Clinical data from the pivotal trials supporting these approvals demonstrated surgical castration levels generally less than 30 ng/dl and both surgical and medical castration levels frequently as low as 15 ng/dl (Sharifi R et al, 1990). Variations in testosterone assay procedures may still confound the clinical interpretation of levels near the 50 ng/dl range, however (see section 6.1, above).

6.6

Directions for Use .

Refer to section 21.0, below, for reviewer’s comments regarding the Dosage and Administration section of the proposed labeling.

7.0 Descrt”ption of Clinical Data Sources

This NDA supplement contains the reports of two clinical trials:

Study #M93-013: “Safety and Efficacy Study of ^aFour-Month Depot Formulation of Leuprolide in Patients with Stage D2 Prostatic Adenocarcinoma,” an uncontrolled pivotal safetY/efficacy trial in 49 target population patients;

--

S[udy #M93- 102: “Pharmacokinetics of a Four-Month Depot Formulation of Leuprolide in Prosta~e Cancer Patients, ” an uncontrolled human pharmacokine[ics study designed ^to measure plasm.1 leupmlide levels for 20 weeks following a single IM injection of t~ Lupron DePot-4?donth 30 mg formulation in 24 orchiectomized prostate cancer patients---

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8.0 Clinical Studies

Page

12 .

8.1

8.1.1 8.1.1.1

Indkation ,

For the palliative treatment of advanced pmstatic cancer when orchieetomy or estrogen administration are either

not indicated or unacceptable to the patient.

Reviewer’s Trial #1: Sponsor’s Protocol #M93-013

(Protocol date April 1993; Amendment #1 incorporated January 1994)

C)biective/Rationale

_.-

Objective of the study:

To demonstrate the effectiveness – defined as sustained suppression of semm testoster~ne levels to the castrate range during the first 32 weeks of treatment - and safety of the 30-mg formulation injected once every 16 weeks in advanced stage prostate cancer patients.

Rationale for the study:

.—

Since approximately 80% of prostate cancer patients have androgendependent disease,

suppression of serum testosterone to castrate levels may favorably modi$ the course of disease progression. Clinical studies using both the daily SC injection (’Lupron Injection 1 mg/O.2 ml) and the depot IM formulations (Lupron Depot 7.5 mg/vial and Lupron Depot-3 Month 22.5 mg/vial) have demonstrated effective T suppression to castrate levels with maintenance during long-term treatment and potential remission or stabilization of disease, reduced pain, increased daily activity (performance status), and improved quality of life. The 30-mg depot

formulation, with its 16-week dosing interval, is intended to increase patient acceptance of the dosing schedule.

8.1.1.2 Design

.

A Phase 111, open-label, uncontrolled, multicenter clinical trial conducted a~

17 investigation] sites (refer to section 8.1.1.4.1, below).

8.1.1.3 Protocol

8.1.1.3.1

Population

a. Demography

..-

40 male patients with Stage D2 (metastatic) prostatic adenocarcinoma were to be recruited by the principal investigators --

-.

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b.

Inclusion criteria:

(I)

Stage

D2 prostate adenocarcinoma, histologically confirmed, i.e., bone ~etastases, z lymph

node metastasis above the aortic bifurcation, or metastasis to other sites such as

liver or lung *

(2)-

Two

or more clinically measurable or evaluable lesions, including the prostate (if present), skeletal or visceral metastasis and/or lymph node metastasis above the aortic bifurcation;

● ✍

(3) Prestudy serum

T

concentration at least ng/dl;

(f) ECOG performance status O, 1, or 2, per the ECOG Performance Scale: , 0 ==fully active

1 =

ambulatory/able to carry out light or sedenrary work 2- ambulatory/capable of self-care/

up and about more than k of waking hours (5) Recovered from effects of any major surgery;

(6) Signed voluntary informed consent.

c. Exclusion criteria:

(1) Absence of an intact hypothalamic-pituitary-gonadal axis

(e.g., prior orchiectomy, hypophysectomy, or adrenalectomy); . (2) Antineoplastic medication within 4 weeks prior to the initial depot injection or during the study (e.g., estrogen, amiestrogen, proges~ogen, antiandrogen, other steroid treatment, chemotherapy); [Amendment #1 -- incorporated January 1994- permitted antiandrogen treatment during the study after week 32]

(3) Prior GnRH analog treatment;

(4) Current radiation therapy (including implants) to a site of prima~, recurrent, or metastatic disease;

(5) Life expectancy less than 12 months;

--

(6) Underlying disease that would place the patient in additional jeopardy by panicip~ting in the study.

-. -.

--

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8.1.1.3.2

Procedures

a. Specific formulations used in

study:

“=Abbott+3818”: Leuprolide acetate for depot suspension (Lupron Depot-4 Month ):

Lyophilized microsphere of leuprolide (30 mg) incomorated into a biodegradable pol-ylactic acid polymer ( trig) with mannitol . mg);

Lot # 79+23-S2 used in cli,lical+d.

Diluent: 2 ml ampule of solution containing carboxymethylcellulose sodium mg), mannitol ( mg), polysorbate 80 f mg) and water for injecIion, USP;

Lot #79-424-S2 used in clinical triai.

Just prior to injection, the preparation was reconstituted by withdrawing 1.5 ml of the ; diluent from the ampule and injecting it into the vial containing the Iyophilized powder.

After shaking, the resulting suspension was withdrawn into a syringe and injected IM (usually gluteal) using a 22-gauge needle. Injection sites were to be rotatechnd the previous injection site examined at the time of the next injection.

b. Type of experimental controls:

Determinations of serum T levels (primary efficacy endpoint) by a central laboratory Per discussion with Dr. Jean Fourcroy, Urology Medical Officer, HFD-580, and prima~ reviewer of GnRH analogs for use in prostate cancer, these procedures are considered appropriate and adequate as the primary surrogate endpoint for the palliative treatment of advanced stage prostate cancer.

c. Dosage schedule, duration of use, and route of administration:

Lupron Depot 30 mg by IM injection was to be administered every 16 weeks, or . once every 112 days. Based on previous clinical data, this regimen seems appropriate.

d. Desirable concomitant medications: None specified.

8.1.1 .3.3 Endpoints

Efficacy

a. Primary:

. .

--

Serum testosterone ~ and LH levels were determined at baseline and an post-treatment davs 4 and 7, at the end of weeks 2 through 20, 22, 24, 26, 28, 30, 32, and every 16 weeks thereafter, and At ~-hours, 8-hours, and 12-hours following the week-16 depot injection (to assess nrhether a stimulator effect, due to incomplete pituitary_ down-regulatiom=~as present; see section 8.1.1.4.2, pg 26 below) in all subjects. [n a subgroup of patients

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(selected

by their voluntary participation in an “expanded blood collection schedule”), LH and T levels were also determined at weeks 14.5, 15.5, 16.5,30.5, 31.5, and 32.5. Blood samples

were sent to on a weekly basis until all patients conqrleted the first 32 weeks of the study.

*

on-treatment levels of 50 ng/dl or less were considered clinically successful, with individual patients cki.ssifiedas “responders” or “nonresponders” according to whether their serum T level reached 50 rig/ml or less (“castrate”) for two consecutive tests within the first 8 weeks after the

first depot injection. “Responders” were further classified as persistent responders or “escapes”

from successful treatment based on whether their serum T levels exceeded 50 rig/ml on 2 consecutive tests (“escape”) after having achieved castrate levels on 2 consecutive tests.

.-

“Nonresponders” and patients with “escape” from T suppression were continued on study at

the discretion of the investigator. ..

b. Secondary:

(I) Clinical/Tumor Evaluation, by physical examination and tumur lesion evaluation, -- consisting of digital rectal examination (DRE), bone scan, and other imaging

procedures, if necessary, to determine “objective tumor response”:

“Complete response” defined as total disappearance of tumor masses and/or osteoblastic/osteolytic lesions, normalization of all pretreatment laboratory abnormalities (i.e., acid phosphatase elevation, liver function abnormalities) and/or hepatomegaly, and without significant cancer-related weight loss (> 10%), symptom worsening, or performance status deterioration;

“Partial response” defined as reduction (> SOOk)in cross-sectional area of at least one tumor mass or in liver size/function (3o% or greater improvement), with associated non-progression or normalization of all other tumor indicators;

“Objectively stable” defined as no new lesions or significant increase ( > 25°/0) cross-sectional area of measurable lesions or of hepatomegaly ( > 300/0);

non-progression or improvement in osteoblastic/osteol~ic lesions, acid phosphatase, liver function; and without significant cancer-related deterioration in weight (> 100/0), symptoms, or performance status;

in

. .

“Progression” defined as any significant cancer-related deterioration in weight, ‘ - symptoms, performance status, appearance of new areas of malignant disease,

or increase in any previously measurable lesion by > 25°/0cross-sectional area.

.

(2) Serum levels of prostate-specific antigen (PSA) (assayed by

prostaric acid phosphatase (PAP), and alkaline phosphatase (both assayed at

(3) ECOG Performance status assessment. -.

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Safety

a. Clinical studies:

z

History and physical examinations7adverse event/concomitant at baseline and weeks 16 and 32; .

b. Laboratory studies:

Page 16 - .

medication reporting

Routine clinical chemistries, hematology, urinalysis at baseline and weeks 16 and 32; .- c. Indications for removing a patient from the study:

Serum T exceeds 50 ng/dl on two consecutive measurements, i.e., “nonrespons> or

“escape” as defined above (see Primary Efficacy Endpoint). Dropouts not replaced.

.—

S. 1.1.3.4 Statistical analysis plan

-

Study results were to be summarized at the conclusion of 32 weeks of treatment or withdrawal - of all enrolled subjects. All data were summarized using the Statistical Analysis System (SAS

Institute, Inc., Version 6.09), with significance defined for any test as a p-value 0.050 or less (rounded to 3 digits), based on two-tailed tests. For all variables, baseline was deiined as the final value obtained before the statt of study drug administration. On-treatment data were grouped into time intetwals (categorized visits) according to the midpoints between scheduled visits or collection times for each variable. If multiple values were obtained for a hormone variable during an interval, the maximum value was used in analysis; for non-hormone data, the value closest to the scheduled collection time was used.

For pivotal efficacy and safety analyses, the analyzed data were selected using cut-off conventions for the number of days after the second (or last for dropouts) injection. The duration of treatment for any injection was defined to be 112 days, and all analyzed data for any laboratory variable were obtained no later than 112 + 15 = 127 days after the second injection. For clinical response variables, data obtained up to 112 + 43 = 155 days after the second injection were used in analysis.

Summary statistics were calculated for the baseline characteristics of age, race, height, weight, “:

and baseline disease status (time since prostate cancer diagnosis, prior treatments, DRE results, and performance status). The primary efficacy analysis focused on suppression of serum T levels during the first 32 weeks of p-eatment, and estimated the proportion of patients who

~chieved “T suppression” (defined as 50 ng/dl or less for 2 consecutive tests within 8 weeks after the first depot injection) and the proportion of suppressed patignts w’ho experienced

“escapes” from T suppression (defined as T levels greater than ng/dl for 2 consecutive tests after achieving suppressed T levels). One-sided exact 95°/0 confidence bounds were calculated on These estimates using the binomial distribution. Median duratio_n was not estimad, since suppression continued beyond 32 weeks in most patients. Summary statistics were also

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provided for T and LH values at each categorized visit with and without respect to the time of the second injection; at 4-hours, 8-hours, and 12-hours following the week 16 injection; and for the subgroup pafiicipating in the “expanded blood collection schedule” during weeks 14, 14.s, 15,

15.5, and 16. Linear trends were tested across time by repeated measures analysis of variance. . Paired t-tests were used to analyz? mean changes from baseline in T and LH at weeks 16 and 16.5, at weeks 32 and 32.5, and at times O,4-hours, 8-hours, and 12-hours post-dose tier the second injection, to evaluate responses (see section 8.1.1.4.2, pg 26 below).

Secondary efficacy analyses included summarization at weeks 16, 32, and “final visit” of the .- propo~ions of patients with graded outcomes on objective tumor response, and changes from

baseline in prostatic DRE findings, PSA, PAP, and performance status.

8.1.1.4

Results

8.1.1.4.1 Populations enrolled/analyzed -—

During the remitment period (October 1993 through April 1994), 17 investigational sites enrolled a total of 49 men, of whom 45 completed the first 32 weeks of the study and were considered evaluable for the primary efficacy analysis. Sponsor states, “the enrollment goal of 40 was exceeded because 9 patients were enrolled within 4 days after the 40th patient had been dosed” (vol. 8.9, p 01 1). Although the long term phase of the study is ongoing, the last patient completed the initial 32 weeks of treatment in December 1994, and, per prior FDA/sponsor agreement, the efficacy data from only the first 32 weeks of treatment were to be considered pivotal. While all treated patients were analyzed for safety, only the evaluable population was initially analyzed for efficacy. In response to a request for intent-to-treat (ITT) analyses as the basis for all labeling claims (FDA letter 10 sponsor dated 2/21/97), ITT analyses for all efficacy outcomes were submitted as Amendment #5. At the end of the initial 32-week treatment period, 43 patients continued into the long-term treatment period.

The participating investigators are listed below and on the next page.

Investigator Institution Location # Pts Enrolled

Austenfeld Childs Ercole Fowler Kandzari Knoll Kramolowsky

Univ. of Kansas Medical Center Kansas City, KS 2

Brookwood Urology Birmingham, AL 2

St. Paul-Ramsey Medical Center St. Paul, MN 1

Univ. of Mississippi

Med Center Jackson, MS 1

Wesr Virginia University

Ctr. for Urologic Treatment &

The Virginia Urology Center

Morgantown, WV 1

Research Nashville, TN 5

Richmond, VA ~ 8

-

-.

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Investigator Institution Location # Pts Enrolled

—

Krasnow

VA Medical Center Washington, DC I

Lynch . Georgetown University Hospital Washington, DC 2

Ning

Western Urological Associates, PC Denver, CO 2

Patterson - University of Tennessee Memphis, TN 3

Ross Hattiesburg Clinic Hattiesburg, MS 1

Sanfilippo Uro]ogy Associates Birmingham, AL 4

Sharifi University of Illinois/VA Med. Center Chicago, IL 8

Smith Vanderbilt University Nashville, TN 4

Tuttle Clinic for UrologicWellness Lexington, KY 1

Zinner Doctor’s Urology Group Torrance, CA ,3

.-

DEMOGIUW-IICS:

For evaluable patients, 69 inches (range The racial distribution

.—

the mean age was 70 years (range years), mean height inches), and mean weight 172 pounds (range Ibs).

was 5 l“~ Caucasian, 470k Black, and 2% Hispanic. Demographics were essentially unchanged for the ITT population, with 49% Cau&sian (n= 24),- ‘ 490/0Black (n==24J, and 2% Hispanic (n= 1) men enrolled.

Prostate cancer diagnosis occurred at a mean of approximately 7 months (0.6 years) prior to enrollment, with 31/45 (69%) of the evaluable patients having been diagnosed within

3 months, and 43/45 (96%) within 3 years of study entry. One month or more prior to entry, 16/45 (36?40) of the patients had received prostate cancer treatment, which included radiation therapy @l?) alone (4 patients), prostatic resection (TURP) alone (5 patients), radical..

prostatectomy alone (1 patient), ketoconazole alone (1 patient), or combinations of these

~reatments (5 patients). Despite prior treatment, all 16 previously treated patients had qu.difying baseline serum T levels.

DROPOUTS

Patients who completed at least 225 study days and received at least 3 injections were . . considered to have completed the study. At or prior to week 32, 6 patients terminated from

the stud y. During the long-term treatment phase, 17 addition.d patients terminated from the stud). for a total of 23 patients who dropped out by the data cutoff date for the safety update (9/7/96). Pertinent details regarding these patients are noted below.

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